The aryl hydrocarbon receptor (Ah receptor or AhR) is a ligand-inducible transcription factor that mediates a number of important biological and pharmacological processes. 2-(1′H-Indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) (Song et al. 2002, U.S. Pat. No. 6,916,834) is an endogenous ligand for the receptor. ITE can be used to study AhR-mediated biological processes and therapeutic potentials and to treat disorders such as cancer (US 2012/0214853, U.S. Pat. No. 8,604,067, Wang et al. 2013, Cheng et al. 2015), obesity (U.S. Pat. No. 7,419,992), and conditions related to imbalanced actions of the immune system (Quintana et al. 2010, Nugent et al. 2013).
The original ITE synthesis scheme (Grzywacz et al. 2003, U.S. Pat. No. 7,002,019) provided for small-scale synthesis of ITE for initial confirmation of its structural identification (Song et al. 2002, U.S. Pat. No. 6,916,834) and for laboratory-scale biomedical studies. However, the original synthesis scheme is not capable of efficiently producing ITE at levels required for clinical studies in large animals and human subjects or therapies.
The efficiency of intra-molecular cyclization to form a thiazoline ring in the original ITE synthesis scheme (Grzywacz et al. 2003, U.S. Pat. No. 7,002,019) is extremely low and becomes even lower as its synthetic scale increases. The inefficiency of this key step severely limits the efficiency of the entire synthesis. The intra-molecular cyclization is most probably hindered by a neighboring carbonyl group. Due to the presence of the carbonyl group, success using other cyclization reactions is unpredictable.
A new synthesis that efficiently forms a thiazoline or thiazole ring is needed in order to develop an efficient and scalable process for large-scale production of ITE and its structural analogs.